tbuckley/cabot-search huggingface dataset:
Abstract LB039: VHL-deficient renal cell carcinoma displays defective ATM activation and sensitivity to ATR inhibition
Authors: Patrick G. Pilie, Lijun Zhou, Yan-Ting Zhang, Christine Peterson, Daniel McGrail, Yang Peng, Guang Peng, Xiande Liu, Xuesong Zhang, Eric Jonasch
Journal: Cancer Research (2022)

Abstract Introduction: Clear cell renal cell carcinoma (ccRCC) displays genomic instability, but lacks mutations in canonical DNA damage response (DDR) genes. Bi-allelic loss of VHL is a near ubiquitous, truncal event in ccRCC development. Herein, we performed preclinical and clinical analysis to understand how VHL loss impacts DDR pathway activity and how specific DDR deficiencies (DDR-D) may be targeted in ccRCC. Methods: We performed DNA whole exome sequencing (WES) and reverse phase protein array (RPPA) early stage ccRCC tumors. All patients were consented under an IRB-approved protocol for the use of tissue. Transcriptomic and protein analyses of select DDR pathways was performed on in silico data (TCGA). DDR functional assays and ATR inhibitor treatment were performed on preclinical cell line models, and in vivo ATR inhibitor treatment in ccRCC xenografts with varying VHL status. Results: Bi-allelic loss of VHL via mutation in one allele and copy number loss of chromosome 3p was observed in 13/13 patient tumors. Mutations in other genes associated with ccRCC and/or canonical DDR genes were not observed. Despite VHL loss being the only driver mutation, these early stage tumors displayed tumor mutational burden (TMB) similar to ccRCC across all tumor stages (1.1 ± 0.5 mut/Mb). Proteomic analysis of patient tumor versus normal tissue (N=12) revealed significantly different (P&amp;lt;0.05) mean expression level of 218 proteins, including significantly lower phospho-ATM at the autophosphorylated S1981 site and lower phospho-CHK2 at the downstream T68 site. VHL-/- cells display defective binding to and repressed activation of Tip60 (KAT5), a key acetyltransferase that activates ATM kinase and aids in the selection of DNA repair pathways following damage. Lastly, treatment with ATRi (VE-822) of 786-O and 786-VHL overexpressing tumor xenografts showed ATRi was safe and significantly inhibited tumor growth preferentially in the 786-O VHL null model. Conclusions: Here we show in patient tissue and preclinical models that VHL biallelic loss results in genomic instability and functional impairment of ATM kinase activity; furthermore, we provide preclinical evidence for selectively targeting the ATR signaling cascade in patients with VHL-deficient kidney cancer. Clinical trials of ATR inhibitor based therapy in patients with advanced cancer, including ccRCC, are underway (e.g. NCT04266912). Citation Format: Patrick G. Pilie, Lijun Zhou, Yan-Ting Zhang, Christine Peterson, Daniel McGrail, Yang Peng, Guang Peng, Xiande Liu, Xuesong Zhang, Eric Jonasch. VHL-deficient renal cell carcinoma displays defective ATM activation and sensitivity to ATR inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB039.
Abstract 2271: Patient-specific visualization of cancer pathways
Authors: Padmapriya Swaminathan, Casey B. Williams, Tobias Meissner
Journal: Cancer Research (2022)

Abstract ​Introduction: Analysis of whole transcriptomics datasets to quantify gene expression and determine differentially expressed genes has provided valuable information for precision medicine. Evaluating enrichment of specific gene groups and pathways, and visualizing these results is an important step to obtain inferences about patient treatment outcomes, overall survival, drug resistance and therapeutic targets. However, pathway analysis of cancer patient samples in a N-of-1 setting without their respective control (normal) samples remains to be challenging. There is a crucial need for methods and tools to conduct and visualize pathway analysis results in this setting. Methods and Results: Our method focuses on a visualization technique showing patient-specific pathway activation relative to reference populations from The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEX). Patient-specific pathway activity scores are displayed within the respective percentiles and averages of the TCGA and GTEX cohorts to visualize a patient's individual pathway activation profile within the TCGA tumor and GTEX normal reference population. Patient-specific pathway scores are derived from an individual patient's transcriptomic profile and transformed into activity scores for each of 14 cancer pathways. This allows for the comparison of an individual patient’s pathway activation profile with reference samples from TCGA and GTEX. We used PROGENy (Pathway RespOnsive GENes for activity inference) to calculate activity scores for the 14 cancer related pathways. The pathway activity scores of each new tumor sample are scaled using the parameters of scaled pathway activity scores obtained from TCGA and GTEX gene expression data of all cancer tissue types. Finally we visualized the pathway activity scores of each patient sample. Conclusion: Our visualization method is expected to unravel the activation patterns of each of the 14 cancer pathways in our patient samples. Specific pathway genes can then be evaluated in the patient samples to identify causal mutations and their associations with the pathway activity scores hence aid in treatment selection and in the further development of precision medicine therapeutic solutions. Citation Format: Padmapriya Swaminathan, Casey B. Williams, Tobias Meissner. Patient-specific visualization of cancer pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2271.
Abstract 2671: ERAS-601, a potent allosteric inhibitor of SHP2, demonstrates anti-tumor activity in RAS/MAPK-driven tumor models
Authors: Leenus Martin, Roopal Patel, Jingchuan Zhang, Jennifer Yang, Robin Nevarez, Taylor Congdon, Les Brail, Robert Shoemaker
Journal: Cancer Research (2022)

Abstract SHP2 is a non-receptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene. SHP2 transduces upstream receptor tyrosine kinase (RTK) signaling to the RAS/MAPK pathway via its phosphatase-mediated regulation of guanine nucleotide exchange factors (GEFs). The modulation of GEF activity impacts the rate at which KRAS cycles from the inactive GDP-bound state to the active GTP-bound state. ERAS-601 is a potent, selective small molecule allosteric inhibitor of SHP2. ERAS-601 potently inhibits the wild type SHP2 protein with a biochemical IC50 of 4.6 nM. ERAS-601 is a selective SHP2 inhibitor and demonstrates no appreciable inhibition against any off-target kinase or phosphatase across panels of 300 kinases and 12 phosphatases. ERAS-601 inhibits the loading of active GTP-bound oncogenic RAS and inhibits RAS/MAPK pathway signaling as measured by pERK1/2 inhibition and DUSP6 mRNA. ERAS-601 demonstrates anti-proliferative activity across a panel of human cancer cell line models with oncogenic alterations in the RAS/MAPK pathway. In a mouse in vivo study, ERAS-601 achieves substantial systemic exposure and demonstrates inhibition of ERK1/2 phosphorylation and DUSP6 mRNA levels in the NCI-H358 xenograft model. ERAS-601 also inhibits tumor growth in multiple RAS/MAPK-driven CDX and PDX models that harbor EGFR, KRAS, BRAF Class III, and NF1LOF mutations. ERAS-601 is a potent and selective allosteric SHP2 inhibitor that demonstrates anti-tumor activity in vitro and in vivo and is currently being studied as a monotherapy in an ongoing Phase 1 clinical study in patients with advanced or metastatic solid tumors (FLAGSHP-1, NCT04670679). Citation Format: Leenus Martin, Roopal Patel, Jingchuan Zhang, Jennifer Yang, Robin Nevarez, Taylor Congdon, Les Brail, Robert Shoemaker. ERAS-601, a potent allosteric inhibitor of SHP2, demonstrates anti-tumor activity in RAS/MAPK-driven tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2671.
Abstract 1821: SPTBN1 Is a potential target to prevent progression of steatohepatitis to hepatocellular carcinoma
Authors: Xiaochun Yang, Shuyun Rao, Xiyan Xiang, Kazufumi Ohshiro, Patricia Latham, Kirti Shetty, Lopa Mishra
Journal: Cancer Research (2022)

Abstract Background: Nonalcoholic steatohepatitis (NASH) is a risk factor for the development of hepatocellular carcinoma (HCC). β-spectrin, encoded by SPTBN1, is associated with HCC. The goal of this study was to evaluate the hepatocyte-specific roles of SPTBN1 in NASH and HCC using mouse models. Methods: We investigated the effect of knocking out Sptbn1 specifically in the liver in mice (LSKO mice). We examined the effect of diets that promote NASH—a high-fat diet (HFD) or Western diet (WD)— and the outcomes of HCC induced by diethylnitrosamine (DEN). Based on the phenotypes of these mice, we examined the therapeutic effects of knocking down Sptbn1 using siRNA. Results: We found LSKO mice were protected from HFD-induced obesity and NASH. Control mice administered siRNA targeting Sptbn1 were protected from developing NASH when placed on a HFD, and NASH phenotypes triggered by WD were reduced by administration of siRNA targeting Sptbn1. LSKO mice appeared to be protected from HFD-induced HCC: One of four HFD control mice developed liver tumors, but none of the three LSKO mice did. HFD-induced HCC is rare in mice, therefore we evaluated DEN-induced HCC. LSKO mice subjected to DEN with or without WD had less severe cancer than did wild-type mice. Compared to the HCC in the control mice, the number of liver tumors in the LSKO mice was lower, the size of the tumors was smaller, and the tumors were less proliferative based on KI67 staining intensity. Furthermore, overall liver pathology was reduced. Conclusions: These data suggest that SPTBN1 is a potential target for therapeutic intervention to treat NASH and prevent progression to HCC. Because other injected siRNA therapies are approved to treat liver diseases, a siRNA-based therapy targeting SPTBN1 could translate into clinical trials. Citation Format: Xiaochun Yang, Shuyun Rao, Xiyan Xiang, Kazufumi Ohshiro, Patricia Latham, Kirti Shetty, Lopa Mishra. SPTBN1 Is a potential target to prevent progression of steatohepatitis to hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1821.
Abstract 3744: Differential Orthopedia Homeobox (OTP) expression in pulmonary carcinoids is associated with changes in DNA methylation
Authors: Laura Moonen, Lise Mangiante, Daphne J. Leunissen, Lisa M. Lap, Aurelie Gabriel, Lisa M. Hillen, Guido M. Roemen, Alexander Koch, Manon van Engeland, Anne-Marie C. Dingemans, Matthieu Foll, Nicolas Alcala, Lynnette Fernandez-Cuesta, Jules L. Derks, Ernst-Jan M. Speel
Journal: Cancer Research (2022)

Abstract Introduction: Limited number of tumor types have been examined for Orthopedia Homeobox (OTP) expression. In pulmonary carcinoids, loss of expression is a strong indicator of poor prognosis. Here, we investigated OTP expression in 37 different tumor types, and the association between OTP expression and DNA methylation levels in lung neuroendocrine neoplasms. Methods: We analyzed publicly available multi-omics data (whole-exome-, whole-genome-, RNA sequencing, Epic-850K-methylation array) of 58 typical-, 27 atypical carcinoids, 69 large cell neuroendocrine carcinoma and 51 small cell lung cancer patients and TCGA (The Cancer Genome Atlas) data of 33 tumor types. 850K-methylation analysis was cross validated using targeted pyrosequencing on 35 carcinoids. Results: Results showed bimodality of OTP expression in carcinoids (OTPhigh versus OTPlow group, likelihood-ratio test p=1.5x10-2), with the OTPhigh group specific to pulmonary carcinoids while absent from all other cohorts analyzed. Significantly different DNA methylation levels were observed between OTPhigh and OTPlow carcinoids in 12/34 OTP infinium probes (fdr&amp;lt;0.05 &amp; β-value effect size&amp;gt;0.2). Overall, OTPlow carcinoids harbor a high DNA methylation level as compared to OTPhigh carcinoids. OTPlow carcinoids showed a significantly worse overall survival (logrank test p=0.0052). Gene set enrichment analysis for somatically mutated genes associated with hallmarks of cancer showed robust enrichment of three hallmarks in the OTPlow group, i.e., sustaining proliferative signaling, evading growth suppressor, and genome instability and mutation. Conclusion: High OTP expression is a unique feature of pulmonary carcinoids with a favorable prognosis. In poor prognostic patients, OTP expression is lost, most likely due to changes in DNA methylation levels. Citation Format: Laura Moonen, Lise Mangiante, Daphne J. Leunissen, Lisa M. Lap, Aurelie Gabriel, Lisa M. Hillen, Guido M. Roemen, Alexander Koch, Manon van Engeland, Anne-Marie C. Dingemans, Matthieu Foll, Nicolas Alcala, Lynnette Fernandez-Cuesta, Jules L. Derks, Ernst-Jan M. Speel. Differential Orthopedia Homeobox (OTP) expression in pulmonary carcinoids is associated with changes in DNA methylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3744.
Abstract 2535: Omental preadipocytes support ovarian cancer tumorigenesis by mediating genes important for extracellular matrix reorganization
Authors: Jennifer A. Waters, Mikella Robinson, Samuel F. Gilbert, Ixchel Urbano, Carrie D. House
Journal: Cancer Research (2022)

Abstract Ovarian cancer is the most lethal gynecological malignancy in the United States, with a known predilection for metastasizing to the omentum, a sheet of fatty tissue that encloses the abdomen. While it has been shown that ovarian cancer cells invade towards mature adipocytes in vitro, the contribution of stromal cells that reside in the omentum is not well understood. We hypothesize that preadipocytes, the precursor cells that give rise to omental adipocytes, are important mediators of cancer progression in the omental tumor microenvironment as they have a pro-inflammatory secretome that is distinct from that of mature adipocytes. To evaluate this hypothesis, we tested whether preadipocyte secreted factors altered tumorgenicity of ovarian cancer cells using colony formation and cell viability in vitro and a limiting dilution in vivo in a subcutaneous mouse model. The mouse studies showed that low dilutions of cancer cells require preadipocytes for engraftment and tumor formation. A transplantation assay showed that cancer cells require the presence of preadipocytes for sustained tumor formation capacity. In vitro co-culture assays revealed that preadipocytes secrete factors that increase clonogenicity and extend cell viability in serum-free conditions. To identify signaling pathways induced by preadipocytes we co-cultured cancer cells with either primary human omental preadipocytes or differentiated mature adipocytes derived from the same female donor and performed RNA sequencing and gene set enrichment analysis (GSEA). We identified differentially expressed genes in cancer cells that were unique to preadipocyte co-culture, including DCN, MMP2, COL6A2 and COL12A1, genes involved in extracellular matrix organization. The most significantly upregulated gene was insulin-like growth factor binding protein 5 (IGFBP5), which has functions in insulin-like growth factor signaling and ECM interactions. Ongoing studies using CRISPR edited cancer cells suggest IGFBP5 mediates the enhanced tumorigenesis of cancer cells in the presence of preadipocytes. Our findings highlight the role of preadipocytes in the ovarian tumor microenvironment and implicate IGFBP5 as a preadipocyte-mediated gene. Future studies will determine if there is a link between the upregulation of IGFBP5 and modulation of extracellular matrix proteins that promote cancer progression. Understanding these processes will enable the design of more effective therapies for treating ovarian cancer. Citation Format: Jennifer A. Waters, Mikella Robinson, Samuel F. Gilbert, Ixchel Urbano, Carrie D. House. Omental preadipocytes support ovarian cancer tumorigenesis by mediating genes important for extracellular matrix reorganization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2535.
Abstract 6160: Tie2-mediated AMPK activation by ferritin-based protein C nanoparticles inhibits advanced prostate cancer development through induction of vasodilation
Authors: You Mie Lee, Ji-Hak Jeong, Hyunha Jang, Jihye You
Journal: Cancer Research (2022)

Abstract Prostate cancer (PCa) is one of the most common malignancies and the second-leading cause of cancer-related mortality in men in Western countries. Androgen deprivation therapy (ADT) is an initial systemic therapy for advanced PCa, but almost all cancer eventually becomes castration resistant. Recently, we introduced ferritin-based protein C nanoparticles (PCNs), known as TFG and TFMG, which enhance normalization of the tumor vasculature. However, the exact underlying mechanism how PCNs induces AMP-activated protein kinase (AMPK) activation and anti-tumor activity in castration-resistant prostate cancer (CRPC) remains unknown. Here, we investigated the role of PCNs for CRPC development in endothelial cells. We found that TFMG inhibits prostate cancer castration resistance by activating AMPK through the Tie2-mediated signaling pathway. TFMG treatment increased AMPK phosphorylation at Thr172 and acetyl-CoA carboxylase (ACC) at Ser79 in EA.hy926 cells. TFMG treatment also significantly increased the phosphorylation of endothelial nitric oxide synthase (eNOS) with inducing nitric oxide (NO) production in EA.hy926 cells. In addition, TFMG treatment induced the vasodilatory effect in isolated rat mesenteric resistance arteries (MRAs), which was blocked by NO synthase inhibitor L-NAME. Interestingly, these effects were all abolished by pretreatment with Compound C (an AMPK inhibitor), rebastinib (selective Tie2 Inhibitor), AMPK knockdown using siRNA, or dominant negative AMPKα recombinant adenovirus. Finally, we found that TFMG functionally abrogates CRPC development in mouse model. In summary, TFMG exerted vasodilatation through activating Tie2/AMPK/eNOS signaling in endothelial cells, which leads to the overcoming vasoconstriction induced ADT. This study provides the potential value of TFMG in vasodilation of blood vessels leading suppression of CRPC development. Citation Format: You Mie Lee, Ji-Hak Jeong, Hyunha Jang, Jihye You. Tie2-mediated AMPK activation by ferritin-based protein C nanoparticles inhibits advanced prostate cancer development through induction of vasodilation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6160.
Abstract 4100: Developmental deconvolution for classification of cancer origin
Authors: Enrico Moiso, Alexander Farahani, Hetal Marble, Austin Hendricks, Samuel Mildrum, Stuart Levine, Jochen Lennerz, Salil Garg
Journal: Cancer Research (2022)

Abstract Cancer is a disease manifesting in abrogation of developmental programs, and malignancies are namedbased on their cell or tissue of origin. However, a systematic atlas of tumor origins is lacking. Here we map the single cell organogenesis of 56 developmental trajectories to the transcriptomes of over 10,000 tumors across 33 cancer types. We use this map to deconvolute individual tumors into their constituent developmental components. Based on these deconvoluted developmental programs, we construct a Developmental Machine Learning Perceptron (D-MLP) classifier that outputs cancer origin. The D-MLP classifier (ROC-AUC: 0.974 for top prediction) outperforms classification based on expression of either oncogenes or highly variable genes. We analyze tumors from patients with cancer of unknown primary (CUP), selecting the most difficult cases where extensive multimodal workup yielded no definitive tumor type. D-MLP revealed insights into developmental origins and diagnosis for most patient tumors. Our results provide a map of tumor developmental origins, provide a tool for diagnostic pathology, and suggest developmental classification may be a useful approach for otherwise unclassified patient tumors. Citation Format: Enrico Moiso, Alexander Farahani, Hetal Marble, Austin Hendricks, Samuel Mildrum, Stuart Levine, Jochen Lennerz, Salil Garg. Developmental deconvolution for classification of cancer origin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4100.
Abstract 848: Inhibition of RTK fusion condensates enhances signal perception and promotes drug tolerance
Authors: David Gonzalez-Martinez, Lee Roth, Thomas Mumford, Yael Mosse, Asmin Tulpule, Trever Bivona, Lukasz Jan Bugaj
Journal: Cancer Research (2022)

Abstract Drug resistance remains a significant obstacle in the successful treatment of cancer, highlighting the critical need to understand how oncogenes and cancer drugs impact cell physiology and resistance development. EML4-ALK is a receptor tyrosine kinase (RTK) fusion oncogene that drives 3-7% of lung cancer. Despite potent ALK inhibitors, EML4-ALK+ cancers frequently develop resistance during therapy. Recently, it was discovered that EML4-ALK and other RTK fusions form cytoplasmic protein condensates, and that condensate formation was required for oncogenic signaling. However, whether oncogenic condensates play a role in drug responses is unclear. In this study, we applied an optogenetic technique called ‘functional profiling’ to understand how EML4-ALK condensates impact cell signal transmission and drug response. Using light-stimulated RTKs, we found that EML4-ALK condensates strongly suppress signaling through transmembrane RTKs, including through EGFR, a central receptor in resistance development. Strikingly, treatment with ALK inhibitors (ALKi) rapidly restored and hypersensitized RTK signaling. We found that EML4-ALK condensates suppress RTK signals through sequestration of the downstream adapter Grb2, which is essential for signaling through EGFR and other RTKs. The release of Grb2 from condensates resensitized RTKs within 10s of minutes of ALKi addition. Resensitized RTKs, in turn, caused sporadic RTK activation pulses throughout the cell population, and pulses originated from paracrine RTK signals released by apoptotic neighbors. We found that these paracrine signals counteracted ALK inhibitor therapy and promoted survival and drug tolerance. Blocking paracrine signals through co-treatment of ALKi with inhibitors of either EGFR or matrix metalloproteases enhanced cell killing and minimized long-term drug tolerance. Our study uncovers a role for oncogenic condensates in drug resistance signaling, reveals a novel mechanism for oncogene-induced suppression of RTK signaling, and suggests novel co-therapies to more effectively treat cancers driven by EML4-ALK and possibly other RTK fusions. Our work also demonstrates the potential of functional optogenetic profiling for drug discovery to promote cancer therapy. Citation Format: David Gonzalez-Martinez, Lee Roth, Thomas Mumford, Yael Mosse, Asmin Tulpule, Trever Bivona, Lukasz Jan Bugaj. Inhibition of RTK fusion condensates enhances signal perception and promotes drug tolerance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 848.